Project Summary/Abstract This application to join the Consortium for the Study of Chronic Pancreatitis, Diabetes and Pancreas Cancer (CSCPDPC), seeks to examine the role of the immune system and of hormonal factors in chronic pancreatitis and its relationship to the development of diabetes and pancreas cancer. Our pre-clinical immunological studies suggest a pivotal role for macrophages, cytokines and stellate cells in predicting the development of fibrosis. Our pre-clinical hormonal studies focus on neuromedin U (NMU), which is a neuropeptide with an inhibitory effect on insulin secretion. It is also of interest for its potential effect on macrophages and cytokines and its role in nociception. These observations may provide further insight into the natural history of chronic pancreatitis, and mechanisms for understanding the development of diabetes in the context of pancreas cancer. In response to this RFA, we have formed a strong scientific team with broad complementary expertise in clinical pancreatitis, immunology, and developmental biology. Our proposal is highly responsive to the RFA in several specific ways. (1) As a Clinical Center, we have the experience and capacity to develop and execute standardized multi-center protocols for enrolling cohorts of patients with chronic pancreatitis, diabetes and pancreas cancer. In this proposal, we specifically delineate a protocol for a prospective longitudinal cohort of patients with chronic pancreatitis accompanied with an annotated bio-repository of blood, urine, stool, and secretin stimulated pancreas fluid. We also have available 2 repositories of blood; one for patients with pancreatitis and the other of pancreas cancer, that are available for sharing with the consortium to support retrospective studies. (2) We will develop and validate cytokine profiles that may facilitate diagnosis of chronic pancreatitis and predict likelihood of associated complications. These may also lead to targets to support clinical trials to halt fibrosis. (3) We will develop and validate a serum-based assay of NMU that may help diagnose type 3c diabetes mellitus and pancreatic cancer-induced diabetes. This may lead to novel diagnostic tests to detect pancreatic cancer at earlier stages. The opportunity to further investigate and validate these novel observations in collaboration with other centers remains an exciting opportunity to accelerate research that could change chronic pancreatitis management and its associated complications of pancreatogenic diabetes and pancreas cancer development.